Method of producing vasodilation using certain 3-substituted-quinazoline derivatives

ABSTRACT

WHEREIN R1 is hydrogen or halogen, R2 is hydrogen or methyl, E is oxygen or sulfur, R3 is hydrogen or halogen, and n has a value of from 1 to 6, produce vasodilation in animals.   Certain 3-substituted-2,4(1H,3H)-di-oxo-quinazoline and 3substituted-2-thio-4-oxo(1H,3H)-quinazoline derivatives and pharmaceutically acceptable acid addition salts thereof having the formula

Vidrio 1 Nov. 11, 1975 1 METHOD OF PRODUCING VASODILATION [56] References Cited USING CERTAIN UNlTED STATES PATENTS 3'SUBSTITUTED'QUINAZOUNE 3.274.194 9/1966 Hayao EGO/356.4

DERIVATIVES Horacio Vidrio, Mexico City, Mexico Miles Laboratories, Inc., Elkhart, Ind.

Filed: Mar. 1, 1973 Appl. No: 336,946

Published under the Trial Voluntary Protest Program on January 28. 1975 as document no. B 336946,

Related US. Application Data Continuation-impart of Serl No. 132.911. April 9. 1971, abandoned.

Inventor:

Assignee:

U.S. Cl.v 424/251 lnt. CL A61K 31/305 Field of Search 424/251 Primary E.mminer-Sam Roscn Attorney, Agent, or FirmMyron B. Sokolowski [57] ABSTRACT Certain 3-substituted- 2,4( 1H.3H )-dioxo-quinazo1ine and 3-substituted-2-thio-4-oxo( 1H.3H )-quinazo1ine derivatives and pharmaceutically acceptable acid addition salts thereof having the formula 1 IHcH 1- i Q R N/ke R METHOD OF PRODUCING VASODILATION USING CERTAIN S-SUBSTITUTED-QUINAZOLINE DERIVATIVES CROSS-REFERENCE This application is a continuation-in-part of US. Pat. application Ser. No. 132,9l l, filed on Apr. 9, 1971 which is now abandoned.

BACKGROUND OF THE INVENTION 1. Field of the Invention Vasodilation is defined as an increase in or the widening of the lumen of blood vessel without regard to whether the latter is a member of the arterial or venous part of the circulatory system of animals. One of the principal physiological effects of vasodilation is a net increase of blood flow in the vascular bed of a tissue, organ. or system. Vasodilation can be induced in experimental animals and man by the administration of certain pharmacologically active agents known as vasodilators.

Vasodilation may be a therapeutic objective in certain vasopathies to correct inadequacies of regional blood flow, for example, in the cutaneous, muscular (skeletal or cardiac). or cerebral circulation and to adjust imbalances between tissue requirements and the delivery and removal of metabolic substances by the blood stream. Examples of conditions where vasodilation may be therapeutically desirable are: intermittent claudication, arteriosclerosis obliterans, Raynauds phenomenon, Menieres syndrome, thrombophlebitis, local frostbite, and nocturnal leg cramps.

From a pharmacodynamic standpoint, known vasodi lators may produce alpha adrenergic blockage, stimulate beta adrenergic receptors, or relax smooth muscle directly. Tolazoline and phentolamine are examples of vasodilators which block alpha adrenergic receptors. The latter compounds, however, cause undesirable side effects which are attributable to cardiac and gastric stimulation. Hence, tolazoline and phentolamine have been reported to cause tachycardia, cardiac arrhythmias, abdominal pain, nausea, diarrhea, and aggravation of peptic ulcers. lsoxsuprine and nylidrin are examples of vasodilators which stimulate beta adrenergic receptors. Although both drugs have been proposed for the treatment of a variety of peripheral vascular disorders, they may cause a variety of side effects such as nervousness, dizziness, palpitation, nausea, and vomiting. Among vasodilators which directly relax smooth muscle, papaverine, dioxyline and cyclan-delate are representative. Papaverine and dioxyline, when administered in large doses, have been reported to cause serious arrhythmias because of depression of A-V and intraventrical conduction. Cyclandelate at 200 mg doses causes unpleasant side effects such as headache and dizziness in many cases. For a more detailed summary of the field, refer to: Nickerson, Mark, Vasodilator Drugs, in The Pharmacological Basis of Therapeutics, 4th edition, L. S. Goodman and A. Gilman, editors, New York, MacMillan and Co., 1970, Chapter 34, pages 751-760. The compounds utilized in the method disclosed in the instant application elicit their effects by alpha adrenergic blockade and by direct relaxation of smooth muscle.

2. Description of the Prior Art The following references are indicative of the prior art pertaining to compounds containing the quinazoline nucleus and their pharmacological activity: US. Pat.

LII

No. 3,047,462 (July 3 l 1962 to Maillard et atl.) for 3- substituted-3,4-dihydroquinazol-4-ones possessing antiinflammatory activity; US. Pat. No. 3,248,292 (Apr. 26. 1966 to Minielli and Scarborough) for 2,4- substituted-6,7-dimethoxyquinazoline compounds useful as bronchodilators and antiinflammatory agents; US. Pat. No. 3.59l,695 (July 6. [971 to Ott) disclosing certain CNS-active 4-phenyl-3,4-dihydroquinazolines useful as antidepressants; and US. Pat. No. 3,274,l94 (Sept. 20. 1966 to Hayao et al.) for 3-substituted- 2,4( lH,3H)-dioxoquinazoline compounds having antiinflammatory or sedative properties.

In standard pharmacological treatises. 2,3-disubstituted-quinazolones are described as hypnotics (e.g., see Sharpless, Seth K., Hypnotics and Sedatives, in The Pharmac'olugical Basis of Therapeutics, 4th edition, L.S. Goodman and A. Gilman, editors, New York. MacMillan and Co., l970, Chapter 10, pages 122 and l3 1 The use of the 3-substituted-2,4( lH,3H)-dioxyquinazolines and 3-substituted-2-thio-4-oxo-quinazoline compounds disclosed in the instant application as a method of producing vasodilation in animals has not been reported.

SUMMARY Disclosed herein is a method of producing vasodilation in animals by the administration of an effective amount of certain 3-substituted-2,4( lH.3H)-dioxoquinazoline or 3-substituted-2-thio-4oxo( lH,3H)- quinazoline compounds or pharmaceutically acceptable acid addition salts of either class having the structural formula 0 R1 oo Z n I I 5 3 (J R2 wherein R is hydrogen or halogen, R is hydrogen or methyl, E is oxygen or sulfur, R is hydrogen or halogen, and n has a value of from l to 6.

The following compounds are particularly useful in the method:

6-chlor0-1-methyl-3-[ 3-( 4-phenyll -piperazinyl propyl ]-2 ,4-( lH,3H )-quinazolinedione hydrochloride;

3-[ 5-(4-m-chlorophen yl- [-piperazinyl )-pentyl 2,4( lH,3H)-quinazolinedione hydrochloride,

3-[ 5-(4-phenyll -pipe razinyl )-pentyl -2-thio-4-oxo 1H,3H )-quinazoline dihydrochloride;

3[ 3-(4-m-chlorophen yll-piperazinyl )-propyl ]2- thio-4-oxo( -H,3H )-quin azoline maleate;

3-[ 2-( 4-m-chlorophen yll -piperazinyl )-ethyl]- 2,4( lH,3H )quinazolinedione maleate',

3 3-(4-phenyll -piperazinyl )-propyl]-6-chloro-2- thio-4-oxo( lI-I,3H )-quinazoline hydrochloride;

6-chloro-3-l 2-( 4-phe nyll -piperazinyl )-ethyl]-2,4 lH,3H)-quinazolinedione maleate;

6-chloro-3-[4-( 4-phenyll -piperazinyl )-butyl}-2,4 1H,3H )-quinazolinedione maleate;

6-ehloro-3-[ 3-( 4-m-chlorophenyll -piperazinyl pyropyl]-2,4( lH3H )-quinazolinedione maleate;

6-chloro-3-[ 3-( 4-p-chlorophenyll-piperazinyl propyl]-2,4( lH,3H)-quinazolinedione maleate',

6-chloro-3-[ 5-( 4-phenyll -piperazinyl )-pentyl]-2,4 1H,3H )-quinazolinedione dihydrochloride;

3-[ 3-( 4-phenyl- 1 -piperazinyl J-propyl1-6-chloro-l4 lH.3H)-quinazolinedione maleate;

3-[ 6-( 4-phenyll-piperazinyl )-hexyl]-2 .4( lI-I.3H quinazolinedione hydrochloride; 3-[3-(phenyl-lpiperazinyl)-propyl]-2.4( 1H.3H) quinazolinedione hydrochloride hydrate.

The synthetic scheme of preparing the above compounds is described by S. Hayao. U.S. Pat. 3.274.194. issued Sept. 20. 1966 and entitled Quinazoline Deriv ati es. As disclosed in the latter. compounds of Formula l are prepared by reacting a corresponding aminobenzamide in a suitable solvent with phosgene or thiophosgene. The o-aminobenzamides which are used as the primary starting materials may be prepared from a primary amine and isatoic anhydride or a substituted derivative thereof. according to Clark and Wagner. J. Org. Chem. 9: 55 I944). The synthesis is illustrated below in the following sequence of equations:

Compounds of Formula I can be isolated as crystalline salts as hydrochlorides. maleates. or other nontoxic acid salts.

The method of producing vasodilation in animals comprises administering to said animals an effective amount of a compound selected from the group of structures and nontoxic acid addition salts thereof represented by Formula I. The compounds can be administered orally or parenterally in doses ranging from to 150 mg/kg. Therapeutic doses of the compounds may range from 150 to 300 mg/day for oral administration and 5 to mg/day for parenteral administration.

An important pharrnacodynamic aspect of this invention is that the vasodilation is effected both by alpha adrcnergic blockade and direct smooth muscle relaxation.

Dose forms of compounds of Formula I can be conveniently prepared by combining the compounds with pharmaceutically acceptable vehicles generally used in the pharmaceutical art. The doses can be prepared in a l J solid or liquid state for oral. parenteral or intravenous R k H N (CH- 1 R administration.

| 0 DESCRIPTION OF THE PREFERRED 5 EMBODIMENTS EXAMPLE 1 4 (a) COCl Production of Vasodilation in Mice by Certain 1 NH (CH n R Quinazoline Derivatives Compared to Reference (b) CSCl Vasodilators and LD Data H R The production of vasodllatlon in mice by the quinazoline derivatives listed in Table I was compared to vasodilation produced by known vasodilators, zolertine. l (CH phentolamine. and papaverine. In these tests, com- R 2 n pounds were administered orally at graduated doses of 10. 30, and 100 mg/kg to groups of 10 mice. Indication I O of vasodilation was a discernable reddening of the tail 2 within 30 minutes of ad ministration of a given test com- R pound. Table l summarizes the results of these tests. In

each case. the minimum dose which produced vasodilation is reported. 1 LD data refer to intraperitoneally administered R 2 n doses.

TABLE I Z Minimum doses required to produce vasodilation in mice of certain quinazoline compounds and reference vasodilators; LD Data In the above equations and formulae. R IS A I R R E and R, R and R are as defined for Formula I. supra. R

COMPOUND MINIMUM DOSE LD,-...

(mg/kg) R and Position R2 n E R and Position A FOR (mg/kg) VASODILATION Cl (m -CH;, 3 0 H H0 2150 H H s 0 Cl(metal HCl It] 1470 H H 5 s H ZHCI IU 215 H H 3 S Climeta) iCHCOgH'g 31) 68k! H H 2 0 cu meta) lCHCO- Cl 3 m0 765 C1 (I H 3 s H HCI mu 1000 (I (6) H 2 0 H (CHCOJHH In 680 CI (6) H 4 0 H (cncogHl 30 680 CI (61 H 3 a Cllmetal (CHC H) mu 147a CI (in H 3 0 CKPui'ill (CHCOQHIB 10a 1474 Cl (6) H 5 0 H 2Hc1 30 I471 61 (a) H 3 0 H ICHCO HJ IOU mm -continued COMPOUND MINIMUM DOSE LD (mg/kg) R and Position R n E R and Position A FOR (mg/kg) VASODILATION H H h H HCI I00 H70 H H 3 0 H HCI-H O 40 Zolertine Phentolamine {(10 Papa\erine I00 EXAMPLE 2 Vasodilator Activity in the Perfused The femoral bed of anesthetized dogs was perfused with the animals own blood by means of a constant output pump. Perfusion pressure measured distally to the pump was taken as an indication of peripheral resistance. Test compounds and reference vasodilators were administered by intraarterial infusion at a rate of 0.33 ntg/min for a total of 5 mg.

The results of these tests in summarized in Table ll. In Table II. Compound A refers to 6-chloro-3[2-(4- phenyll -piperazinyl )ethyl ]-Z,4( lH.3H )-quinazoline dione maleate, Compound B refers to 3-[5-(4-phenyll-piperazinyl) pentyll-Z-thio-4-oxo-quinazoline dihydrochloride, Compound C is 3-[ 5-(4-m-chlorophenyl-lpiperazinyhpentyl] 2,4( lH,3H)-quinazoline hydrochloride, and Compound D represents 3-[3-(phenyl l' piperazinyl)propyll-2.4( lH,3H) quinazolinedione hydrochloride hydrate. Reference vasodilators utilized for comparison are zolertine (referred to as Compound E), isoxuprine (referred to as Compound F), and papaverine (referred to as Compound G).

TABLE ll Effect of selected quinazoline compounds on the perfused ferntoral bed of the dog Decrease in Perfusion Pressure. mmHg. at

The method of producing vasodilation using 3-[3- (phenyll -piperazinyl )propyl l2,4( lH,3H )-quinazoline hydrochloride hydrate was compared with phentolamine as a reference by four different methods:

A. determining effect on blood flow in the hind limb of an anesthetized dog upon intraaterial injections of graded doses;

B. determining effect on perfusion pressure in the hind limb of an anesthetized dog perfused with blood at a constant rate upon intraaterial injections of graded doses:

C. determining the antagonism elicited by graded concentrations of the vasoconstriction induced in the isolated perfused rabbit ear by an excess of potassium in the perfusion fluid and D. determining the increase in the temperature of the surface of the ear of unanesthetized rabbits produced by graded intravenous doses.

The results of these tests are shown in Table III which follows wherein the Compound D is 3-[3-(4-phenyl-ll5 piperazinyhpropyl]-2.4( lH.3HJ-quinazolinedione hydro-chloride hydrate.

TABLE Ill Dose necessary to: Compound D Phentolamine Increase blood flou 004 mg/ml .064 mg/ml lllll ml/min, per

method A Decrease perfusion ,00-1 mglml x87 mgrml pressure 20 mm. of

Hg per method B Antagoni'ze by 50') K .088 mg/ml .IJ mglml :5 induced \asoconstriction per method L Increase temperature .073 mglkg 4.0 mglltg h 7 C. per method D EXAMPLE 4 i To determine the alpha adrenergic blocking activity of same quinazolinedione hydrochloride hydrate used in Example 3 compared to that of phentolamine. the ability of both compounds to antagonize responses of the rabbit aortic strip to epinephrine was evaluated The procedure employed was described in J. Pharmacol. Exper. Therap. l08 [29 (1953). Contractions were elicited by adding a fixed concentration of epinephrinc. The test compounds were added at various concentrations and the degree of blockade of the control response was assessed. Concentrations antagonizing such response by were 0.032 mg/ml for the quinazolinedione compound and 0.033 mg/ml for phentolamine used as a reference.

Similar results are obtained when other compounds included in the general formula set forth in the summary of this invention are employed to dilate arteries of animals and thus increase blood flow.

What is claimed is:

l. A therapeutic method of producing vasodilation in an animal in need of such therapy comprising:

administering to said animal an effective dose of a substance selected from the group consisting of compounds having the formula i )Q R1 NL fiT R3 and pharmaceutically acceptable acid addition salts thereof, wherein:

R is selected from the group consisting of hydrogen and halogen; R is selected from the group consisting of hydrogen and methyl; R" is selected from the group consisting of hydrogen and halogen;

E is selected from the group consisting of oxygen and sulfur; and

n is an integer ranging from 1 to 6. inclusive.

2. A therapeutic method of producing \asodilation in an animal in need of such therapy comprising:

administering to said animal an effective dose of a substance selected from the group consisting of compounds having the formula R m di a R I and pharmaceutically acceptable acid addition salts thereof. wherein:

R is selected from the group consisting of hydrogen and chlorine;

R is selected from the group consisting of hydrogen and methyl;

E is selected from the group consisting of oxygen and sulfur;

u is an integer ranging from 1 to 6 inclusive; and

R is selected from the group consisting of m-chloro and p-chloro.

3. A therapeutic method of producing vasodilation in an animal in need of such therapy comprising:

administering to said animal an efi'ective dose of a compound selected from the group consisting of 3-[3(-1-phenyl-l-piperazinylJ-propyll- 2.4( 1H.3H )-quinazolinedione, 3-[ 3-(4-phenyll piperazinyl )-propyl]-2 4( lH 3H l-quinazolinedione hydrochloride. 3-[ 3-( 4-phenyll -piperazinyl propyl]-2,4(1H,b 3H)-quinazolinedione hydrochloride hydrate, and 3-[ 3-( 4-phenyll piperazinyl )-propyl]-2 .4( lH 3H )-quinazolinedione maleate.

4. A method as in claim 2 wherein said compound is o-chlorol methyl-3-[ 3-( 4-phenyll -piperazinyl propyl]-2,4( lH.3H )-quinazolinedione hydrochloride.

5. A method as in claim 2 wherein said compound is 3-[ 5-( 4-m-chlorophenyll -piperazinyl )-pentyl]- 2.4( lH.3H J-quinazolinedione hydrochloride.

6. A method as in claim 2 wherein said compound is 8 3-[ 5-(4-phenyll -piperazinyl )pentyl1-2-thio-4- oxo( lH.3H)-quinaz.oline dihydrochloride.

7. A method as in claim 2 wherein said compound is 3-[ 3-( 4-m-chlorophenyll -piperazinyl l-propyl l-2-thio- 4-oxo( lH.3H l-quinazoline maleate.

8. A method as in claim 2 wherein asid compound is 3-[ 2( 4-m-chlorophenyll -piperazinyl )-ethyl l-H lH 3H )-quinazolinedione maleate.

9. A method as in claim 2 wherein said compound is 3-[ 3( 4-phenyl l-piperazinyl )-propyl -6-chloro-2-thio- 4-oxot lH,3H )-quinazoline hydrochloride.

10. A method as in claim 2 wherein said compound is 6-chloro-3-[ 2.-( 4-phenyll -piperazinyl )-ethyl 2 4( lH.3H )-quinazolinedione maleate.

11. A method as in claim 2 wherein said compound is 6-chloro-3-3-[ 4-( 4 phe nyll-piperazin yl l-butyl 1- 2.4( lH 3H )-quinazolinedione maleate.

12. A method as in claim 2 wherein said compound is 6-chloro-3-[ 3( 4-m-chlorophenyll -piperazinyl propyl]-2.4( lH.3H )-quinazolinedione maleate.

13. A method as in claim 2 wherein said compound is 6-chloro-3-[ 3-( 4-p-chlorophenyll-piperazinyl propyl]-2.4( lH.3H )-quinazolinedione maleate.

14. A method as in claim 2 wherein said compound is 6chloro-3-[ 5-(4-phenyl 1 -piperazinyl )-pentyl]- 2.4( lH 3H)-quinazolinedione dihydrochloride.

15. A method as in claim 2 wherein said compound is 3-[ 3-( 4-phenyl l -piperazinyl )propyl -6-chloro- 2 4( 1H.3H )-quinazolinedione maleate.

16. A method as in claim 2 wherein said compound is 3-[ o-(4-phenyl-l-piperazinyl )-hexyl]-2.4( 1H.3H)- quinazolinedione hydrochloride.

17. A method as in claim 2 wherein said compound is administered orally. 

1. A THERAPEUTIC METHOD OF PRODUCING VASODILATION IN AN ANIMAL IN NEED OF SUCH THERAPY COMPRISING: ADMINISTERING TO SAID ANIMAL AN EFFECTIVE DOSE OF A SUBSTANCE SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA
 2. A therapeutic method of producing vasodilation in an animal in need of such therapy comprising: administering to said animal an effective dose of a substance selected from the group consisting of compounds having the formula
 3. A therapeutic method of producing vasodilation in an animal in need of such therapy comprising: administering to said animal an effective dose of a compound selected from the group consisting of 3-(3-(4-phenyl-1-piperazinyl)-propyl)-2,4(1H,3H)-quinazolinedione, 3-(3-(4-phenyl-1-piperazinyl)-propyl)-2,4(1H,3H)-quinazolinedione hydrochloride, 3-(3-(4-phenyl-1-piperazinyl)-propyl)-2,4(1H,b 3H)-quinazolinedione hydrochloride hydrate, and 3-(3-(4-phenyl-1-piperazinyl)-propyl)-2,4(1H,3H)-quinazolinedione maleate.
 4. A method as in claim 2 wherein said compound is 6-chloro-1-methyl-3-(3-(4-phenyl-1-piperazinyl)-propyl)-2,4(1H,3H) -quinazolinedione hydrochloride.
 5. A method as in claim 2 wherein said compound is 3-(5-(4-m-chlorophenyl-1-piperazinyl)-pentyl)-2,4(1H,3H)-quinazolinedione hydrochloride.
 6. A method as in claim 2 wherein said compound is 3-(5-(4-phenyl-1-piperazinyl)pentyl)-2-thio-4-oxo(1H,3H)-quinazoline dihydrochloride.
 7. A method as in claim 2 wherein said compound is 3-(3-(4-m-chlorophenyl-1-piperazinyl)-propyl)-2-thio-4-oxo(1H,3H) -quinazoline maleate.
 8. A method as in claim 2 wherein asid compound is 3-(2-(4-m-chlorophenyl-1-piperazinyl)-ethyl)-2,4(1H,3H)-quinazolinedione maleate.
 9. A method as in claim 2 wherein said compound is 3-(3(4-phenyl-1-piperazinyl)-propyl)-6-chloro-2-thio-4-oxo(1H,3H) -quinazoline hydrochloride.
 10. A method as in claim 2 wherein said compound is 6-chloro-3-(2,-(4-phenyl-1-piperazinyl)-ethyl)-2,4(1H,3H)-quinazolinedione maleate.
 11. A method as in claim 2 wherein said compound is 6-chloro-3-3-(4-(4-phenyl-1-piperazinyl)-butyl)-2,4(1H,3H)-quinazolinedione maleate.
 12. A method as in claim 2 wherein said compound is 6-chloro-3-(3-(4-m-chlorophenyl-1-piperazinyl)-propyl)-2,4(1H,3H) -quinazolinedione maleate.
 13. A method as in claim 2 wherein said compound is 6-chloro-3-(3-(4-p-chlorophenyl-1-piperazinyl)-propyl)-2,4(1H,3H) -quinazolinedione maleate.
 14. A method as in claim 2 wherein said compound is 6-chloro-3-(5-(4-phenyl-1-piperazinyl)-pentyl)-2,4(1H,3H)-quinazolinedione dihydrochloride.
 15. A method as in claim 2 wherein said compound is 3-(3-(4-phenyl-1-piperazinyl)-propyl)-6-chloro-2,4(1H,3H)-quinazolinedione maleate.
 16. A method as in claim 2 wherein said compound is 3-(6-(4-phenyl-1-piperazinyl)-hexyl)-2,4(1H,3H)-quinazolinedione hydrochloride.
 17. A method as in claim 2 wherein said compound is administered orally.
 18. A method as in claim 2 wherein said compound is administered parenterally.
 19. A method as in claim 2 wherein said dose ranges from 10 mg/kg to 100 mg/kg.
 20. A method as in claim 2 wherein said dose ranges from 150 to 300 mg per day.
 21. A method as in claim 2 wherein said compound is administered in a pharmaceutically acceptable carrier.
 22. A method as in claim 21 wherein said carrier is a solid.
 23. A method as in claim 21 wherein said carrier is a liquid. 